The proposal emanates from studies based upon the so-called "minimal model" of glucose utilization, which allows for simplified assessment of factors which determine glucose tolerance in vivo. In particular, this model allows for the segregation of the role of insulin in glucose tolerance, from factors which determine glucose tolerance independent of a dynamic insulin response. The former includes insulin secretion and insulin-dependent glucose utilization, the latter includes glucose utilization by tissues which are not sensitive to insulin. Previous results have indicated that, in insulin resistant states including Type 2 diabetes insulin-independent mechanisms have increased importance in the determination of fasting glycemia and glucose tolerance. Additionally, insulin-independent mechanisms may be down-regulated in diabetes. Here we propose to evaluate, by 3 separate protocols, the relative importance of insulin independent mechanisms in normal and insulin resistant animals, and animals with insulin resistance and insulinopenia, which may be a model of Type 2 diabetes. A second concept emanating from the minimal model was the importance of "remote" or interstitial insulin in determining insulin-dependent glucose utilization. We have demonstrated that the rate of glucose uptake by the hindlimb is proportional to the insulin level in lymph exiting the hindlimb. This suggests that it is interstitial insulin which represents the signal for glucose uptake by peripheral tissues. Because there is a substantial delay (2-3 hours) between the onset of hyperinsulinemia and glucose uptake, this data indicates that transendothelial insulin transport is rate limiting for insulin action in vivo. Protocols are designed to examine whether lymph insulin does, in fact, reflect insulin in interstitial fluid. Additional studies will examine the kinetics of insulin transport (by pharmacokinetic modeling) as well as the kinetic relationships between plasma insulin, interstitial insulin and glucose utilization. These studies, and other utilizing labelled insulin and insulin analog molecules, will determine the specificity of transendothelial insulin transport. Additionally, the hypothesis will be tested that the kinetics of insulin transport across endothelium can be changed by hyperinsulinemic insulin resistant states, and insulinopenic, insulin resistant diabetic states. Finally, the physiological significance of the delayed transendothelial transport will be examined by asking whether the magnitude of the biphasic insulin response in plasma has evolved to optimize the rate of increase in insulin in the remote, interstitial compartment where insulin acts.